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解剖位置决定了黑色素瘤的致癌特异性

Joshua M Weiss ^1,2,3, Miranda V Hunter ², Nelly M Cruz ²

¹Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, NY, USA.
²Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
³Cell and Developmental Biology Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA.
⁴Developmental Biology, The Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁵Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁶Computational and Systems Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁷Physiology, Biophysics & Systems Biology Graduate Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA.
⁸QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁹Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.
¹⁰Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
¹¹Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
¹²Royal North Shore Hospital, Sydney, New South Wales, Australia.
¹³John Curtin School of Medical Research, Australian National University, Acton, Australian Capital Territory, Australia.
¹⁴Centre for Cancer Research, Westmead Institute for Medical Research, The University of Sydney, Westmead, Sydney, New South Wales, Australia.
¹⁵New South Wales Health Pathology, Sydney, New South Wales, Australia.
¹⁶School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
¹⁷Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁸Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁹Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
²⁰Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, Odense, Denmark.
²¹Microchemistry and Proteomics Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
²²Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
²³Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
²⁴Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
²⁵Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
²⁶Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
²⁷Weill Cornell Medicine, New York, NY, USA.
²⁸Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. whiter@mskcc.org.

⁰Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, NY, USA.

Nature +

|

2022年三月31日

在PubMed上查看摘要

概括

细胞的位置决定了癌症的易感性. 由CRKL放大和HOX13基因驱动的状黑色素瘤的特定基因程序促进了肢体瘤的生长.

科学领域

癌症学
遗传学
发育生物学

背景情况

瘤突变并不总是导致癌症,这表明细胞反应取决于环境.
细胞的特定解剖位置可能会影响其对瘤基因的敏感性.
皮肤和瘤亚型具有不同的起源和遗传特征.

研究的目的

研究解剖位置在决定细胞对瘤变化的反应中的作用.
鉴定皮肤黑色素瘤和皮黑色素瘤之间的遗传差异.
阐明状黑细胞对某些癌基因的特定敏感性背后的机制.

主要方法

人类皮肤和状黑色素瘤样本的DNA测序.
开发转基因斑马鱼模型研究瘤基因驱动的瘤形成.
来自斑马鱼不同解剖位置的黑色素细胞的RNA分析.
取消CRKL驱动程序的功能研究.

主要成果

皮肤黑色素瘤中的BRAF突变和状黑色素瘤中的CRKL放大.
在斑马鱼模型中,CRKL驱动的瘤主要形成在上,是肢体的前体.
甲状腺黑细胞具有与CRKL协同作用的位置性身份基因程序 (HOX13).
这种协同作用增强了类似胰岛素的生长因子 (IGF) 信号,推动了瘤的形成.
破坏CRKL驱动的程序消除了状黑色素瘤的解剖特异性.

结论

在黑色素瘤中,解剖位置是癌基因易感性的关键决定因素.
涉及HOX13和CRKL的一种独特的转录状态使它们易受特定的瘤性攻击.
了解位置效应对于向癌症治疗至关重要.

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